PCK2
Inhibition Reverses Cisplatin Resistance of Non‐Small Cell Lung Cancer by Triggering Ferroptosis
Jing Liu, Ziyan Wang, Chen Gu, Yili Chen, Yang Yang, Jianjie Zhu, Yihua Zhang, Yuna Shao, Xiaodong Pang, Yujie Ge, Huiwen Qian, Jian‐an Huang, Zeyi Liu, Yuanyuan Zeng, Cheng Ji ABSTRACT
Non‐small cell lung cancer (NSCLC) accounts for ~85% of lung cancers, with platinum‐based chemotherapy as the main treatment. Ferroptosis has been implicated in cancer chemoresistance, yet the molecular mechanisms linking metabolic reprogramming to ferroptosis‐mediated cisplatin resistance in NSCLC remain elusive. In this study, we found that phosphoenolpyruvate carboxykinase 2 (PCK2), a metabolic reprogramming enzyme, was significantly upregulated, and its overexpression enhanced ferroptosis resistance, thereby promoting cisplatin chemoresistance. Mechanistically, RGB‐286638 free base (RGB) inhibits PCK2 expression by directly binding to its R454 site to activate ferroptosis in cisplatin‐resistant cells and restores cisplatin sensitivity both in vitro and in vivo. Targeting PCK2 with RGB provides a promising strategy to overcome chemoresistance, facilitating improved clinical interventions for NSCLC.